Patients with epilepsy are more likely to develop depression, and patients with depression are also at an increased risk of developing epilepsy. This co-morbidity poses a serious health concern, as the presence of both diseases predicts a diminished response to treatment and lowered quality of life. A rat model of epilepsy and depression co-morbidity has been developed to study the interaction between these two diseases; rats selectively bred for depression-like phenotypes are more susceptible to limbic seizures than their depression-resistant counterparts. The goal of this project is to further characterize and validate this model of co-morbidity, and to identify genes that contribute to both the depression-like and seizure susceptible phenotypes in these selectively bred rats. This research will provide new information on the genetic factors responsible for the interaction between these diseases and has potential clinical relevance for drug development, screening, and targeted treatment of patients suffering from epilepsy and depression. Specific Aim 1: To assess epileptogenesis in depression-susceptible and depression-resistant rat lines. Rats bred for susceptibility to a depression-like phenotype are expected to develop seizures more rapidly than depression-resistant rats (i.e., show an increased rate of epileptogenesis). This will be investigated using electrical hippocampal kindling. Specific Aim 2: To define chromosomal regions containing genes that influence depression-like phenotypes and seizure susceptibility. Quantitative trait loci analysis will be used to map activity in the forced swim test and latency to seizure following pilocarpine administration to distinct chromosomal regions harboring genes responsible for the depression and epilepsy-like phenotypes in selectively bred rats. Specific Aim 3: To identify genes that are differentially expressed in rat strains selectively bred for susceptibility or resistance to a depression-like phenotype. Expression microarrays will be used to identify genes with differential hippocampal expression between lines. These genes will be mapped onto the critical chromosomal regions found in Aim 2 to generate a list of candidate genes responsible for depression-like and seizure susceptible behaviors. The goal of this project is to identify genes that are involved in both epilepsy and depression-like behaviors, using a rat model. Further development of our animal model and identification of genes that are common to both disorders will suggest new treatment options for patients with epilepsy and depression. Studying this model will also provide a tool for screening new medications for safety and effectiveness.